Actas Dermosifiliogr. 2020;111(9):734---742

NOVELTIES IN DERMATOLOGY

Cutaneous Manifestations in the Context of SARS-CoV-2

Infection (COVID-19)�

J.M. Carrascosa,∗ V. Morillas, I. Bielsa, M. Munera-Campos

Servicio de Dermatología, Hospital Universitari Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Barcelona,

Spain

Received 12 May 2020; accepted 22 August 2020

Available online 15 October 2020

KEYWORDSCOVID-19;SARS-CoV-2 infection;Skin;Acral lesions;Blister;Urticaria;Exanthema;Livedoid lesions;Viral diseases

Abstract The coronavirus 2019 (COVID-19) pandemic, caused by severe acute respiratory

syndrome coronavirus 2 (SARS-CoV-2), has had enormous health, economic, and social conse-

quences. The clinical spectrum of cutaneous manifestations observed in patients with COVID-19

is both heterogeneous and complex. To date, reports have identified 5 main categories: acral

lesions, vesicular rashes, urticarial rashes, maculopapular rashes, and livedoid and necrotic

lesions. However, these will probably be modified as new information comes to light. Cutaneous

manifestations associated with COVID-19 probably reflect the activation of pathogenic pathways

by the virus or a response to inflammatory processes, vascular or systemic complications, or

even treatments. Familiarity with the cutaneous manifestations of COVID-19 may enable early

diagnosis or help guide prognosis.

© 2020 Published by Elsevier Espana, S.L.U. on behalf of AEDV. This is an open access article

under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

PALABRAS CLAVECOVID-19;SARS-CoV-2;Piel;Acral;Vesículas;

Manifestaciones cutáneas en el contexto de la infección por SARS-CoV-2 (COVID-19)

Resumen La pandemia por SARS-CoV-2 ha causado un gran impacto desde el punto de vista

sanitario, económico y social. La semiología dermatológica se ha demostrado heterogénea y

compleja. En la actualidad se han definido cinco grupos principales de manifestaciones cutáneas

asociadas a la COVID-19: lesiones acrales, exantemas vesiculares, erupciones urticariales, exan-

temas maculopapulares y lesiones livedoides/necróticas. Sin embargo, es probable que esta

� Please cite this article as: Carrascosa JM, Morillas V, Bielsa I, Munera-Campos M. Manifestaciones cutáneas en el contexto de la infección

por SARS-CoV-2 (COVID-19). Actas Dermosifiliogr. 2020;111:734---742.∗ Corresponding author.

E-mail address: jmcarrascosac@hotmail.com (J.M. Carrascosa).

1578-2190/© 2020 Published by Elsevier Espana, S.L.U. on behalf of AEDV. This is an open access article under the CC BY-NC-ND license

(http://creativecommons.org/licenses/by-nc-nd/4.0/).

Cutaneous Manifestations in the Context of SARS-CoV-2 Infection (COVID-19) 735

Urticaria;Exantema;Livedo;Virosis

clasificación se modifique en el futuro. La clínica cutánea es probablemente el reflejo de dis-

tintas vías patogénicas con implicación variable de la infección vírica, del proceso inflamatorio,

de las complicaciones vasculares o sistémicas de la enfermedad o incluso de los tratamientos

administrados. El conocimiento de las manifestaciones cutáneas puede permitir un diagnóstico

precoz o incluso servir como marcador pronóstico.

© 2020 Publicado por Elsevier Espana, S.L.U. en nombre de AEDV. Este es un artıculo Open

Access bajo la licencia CC BY-NC-ND (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Introduction

In December 2019, cases of pneumonia of unknown originwere reported in Wuhan, China. These were subsequentlyfound to be caused by a new pathogen, severe acute respi-ratory syndrome coronavirus 2 (SARS-CoV-2), isolated fromthe lower respiratory tract of affected patients.1

This is the third time in the last few decades that a coro-navirus endemic in animal species has made the jump tohumans.1 Prior to these jumps, coronaviruses (HCoVs) alfa(HCoV-229E and HCoV-NL63) and beta (HCoV-JHKU1, HCoV-OC43) had been identified as endemic in humans. In 2002,there was an outbreak in China of a coronavirus that causedsevere acute respiratory syndrome (SARS). The virus wasnamed SARS-CoV, and mortality was reported at around 10%.In 2012, a respiratory syndrome caused by a coronavirus fromthe Middle East (MERS-CoV) was identified in Saudi Arabia.In this case, the mortality was 35%. SARS-CoV-2 is the newmember of this group. Disease associated with the virus isdenoted coronavirus disease-19 (COVID-19), thus avoidingany geographical qualification. The virus propagated out ofcontrol and the outbreak was declared a pandemic by theWorld Health Organization (WHO) in March 2020.

The most frequent manifestations of infection with SARS-CoV-2 include fever, dry cough, and dyspnea; less frequentare odynophagia, gastrointestinal symptoms, and anosmia orageusia. A high proportion of patients develop pneumonia,often bilaterally, and this may lead to respiratory failure andthe need for respiratory support in more than 6% of cases.2

Around 30% will require admission to hospital, and 5% to 10%will need admission to intensive care units (ICUs). Mortalityvaries widely, from around 2% to somewhat greater than 10%in some countries,3 and it appears higher in older individ-uals and those with comorbidities and marked respiratorycompromise.

Infection can also occur without symptoms or with verymild symptoms, and patients with these forms are probablypotent vectors helping to spread infection.

Pathogenesis

From the pathogenic point of view, the immune responsetriggered by infection with SARS-CoV-2 may result in harmfuleffects, such as endothelial cell dysfunction and activationof coagulation pathways; this may explain the cardiovascu-lar and thrombotic complications that affect a subgroup ofpatients.4

The corona (or crown) of this virus is formed fromprotruding glycoproteins that form spikes. These struc-tures are what enables the virus to establish itself in thehost. The infection process occurs by binding to receptorsof angiotensin converting enzyme 2 (ACE2), a membraneprotein expressed in the cardiovascular system, kidneys,gastrointestinal system, and lungs. This enzyme is impli-cated in activation of the renin-angiotensin-aldosteronesystem (RAAS). ACE2, in normal conditions, counteracts theactivity of the ACE enzyme by reducing the amount ofangiotensin II (vasoconstrictor) and increasing the vasodila-tory metabolites of the RAAS. According to preliminarydata, when SARS-CoV-2 infection occurs, ACE2 appears to bedownregulated and this process is implicated in the devel-opment of acute lung lesions.5 Contact between these 2proteins (spikes on the virus and ACE2) permits anchor-ing via the transmembrane protease, serine 2 (TMPRSS2)enzyme, setting in motion a molecular cascade by whichthe virus is able to enter the cells. The main target isthe respiratory tract, and, in particular, the alveoli, wherebinding to the ACE2 receptors on pneumocytes occurs.Alveolar epithelial cells and macrophages release proinflam-matory cytokines that attract neutrophils and macrophages.In normal conditions, these are components of immune pro-tection. However, in some patients, the immune responseis pathogenic or dysregulated, with exaggerated releaseof IL-1�, IL-6, and IFN-�; epithelial cell apoptosis; andincreased vascular permeability. These events may leadto the development of SARS, in which obliteration of thealveoli, formation of typical hyaline membranes, and hyper-plasia of type II pneumocytes have been observed. Theterms coined for this exaggerated inflammation are cytokine

storm or cytokine release syndrome. Blood workup oftenshows lymphopenia, with elevated values for inflammatoryindicators (C-reactive protein, ferritin, d-dimer, IL-6, andprocalcitonin).2

In addition, the pattern of tissue damage observed in lungsamples and some skin samples taken from patients withsevere COVID-19 suggest occlusive microvascular damagemediated by complement activation of both the alterna-tive pathway and the lectin-associated pathway. Capillarydamage has been found with extensive deposition of theC5b-9 membrane attack complex, C4d, and mannose-binding lectin-associated serine protease 2 (MASP2) in thelungs. There have also been reports of a pattern of microvas-cular thrombotic disease mediated by complement in theskin of patients similar to that seen in livedo racemosalesions and retiform purpura, with C5b-9 and C4d deposi-tion. Activation of these mechanisms and interference in

736 J.M. Carrascosa et al.

ACE2 function in target tissues due to viral action leads toan increase in angiotensin II, associated with greater inflam-mation and oxidative stress. The release of these reactiveoxygen species and interference in antioxidant activity mayincrease complement activiation.6

Skin Manifestations

Articles published at the start of the pandemic in Chinaconsidered skin manifestations as a minor and nonspecificsign, with rash reported in 0.2% of patients.7 However, thisobservation may presumably have been conditioned by thelack of dermatologists caring for patients affected by COVID-19 at the start of the outbreak. Recalcati,8 who was adermatologist, observed skin manifestations in 20.4% of agroup of 88 patients with COVID-19; in some cases, thesemanifestations were present from the start whereas oth-ers appeared during or after admission to hospital. Hedouet al.,9 in response to the aforementioned article, reportedskin lesions attributable to COVID-19 in 4.9% of patientswith a positive polymerase chain reaction (PCR) test resultin a series of 103 patients. However, the real incidence ofskin manifestations in infection by SARS-CoV-2 is not known,bearing in mind that at the time, the focus was on patientswith severe signs or symptoms, and diagnosis was made inmany patients with no or limited symptoms following a tele-phone call by the patient to the primary care physician,without any face-to-face visits, and therefore no skin exam-ination (Table 1).

Fernández-Nieto et al.10 reported difficulties facing der-matologists for taking samples and even clinical images in apandemic that requires rigorous isolation measures, and thisis a barrier to conducting reliable epidemiological studies.For these procedures, transparent bags can be consideredboth for transporting photographic equipment and the toolsnecessary for taking biopsies. The COVID-19 pandemic repre-sents a completely new scenario for dermatologists, and thissituation may be prolonged, depending on how the pandemicprogresses.

The recent article by Galván et al.,11 supported by theSpanish Academy of Dermatology and Venereology (AEDV),reported heterogeneous and complex skin manifestationsassociated with COVID-19 infection. The authors studied agroup of 375 patients prospectively enrolled in several Span-ish hospitals for 2 weeks during the peak of the pandemic.They identified 5 main clinical patterns related to COVID-19:acral areas of erythema with vesicles or pustules (pseu-dochilblain pattern) (19%), vesicular rashes (9%), urticariallesions (19%), maculopapular lesions (47%), and livedo ornecrosis (6%).

The following paragraphs describe the most importantclinical features and diagnostic and prognostic implicationsin patients with SARS-CoV-2 infection.

Acral or Acroischemic Lesions

The acral pseudochilblain pattern of lesions, reported byGalván et al.11 as acral, erythematous, and edematouslesions, with formation of vesicles and pustules, are per-haps the most characteristic skin lesions associated withthe SARS-CoV-2 pandemic. The description and reporting

Figure 1 Acral pseudochilblain papule.

of these lesions initially occurred outside academic cir-cles in an informal fashion in medical or dermatologicalsocial media, based on shared images from family members,acquaintances, and colleagues. The first case publishedreported an adolescent aged 13 years who developed pur-puric lesions on the feet prior to developing systemicsymptoms such as fever, muscle pain, and headache, in afamily with suspected cases of COVID-19 infection at thetime the pandemic in Italy was spreading rapidly.12 How-ever, no specific microbiological studies were performed.In the article, the authors mentioned the existence of anepidemic of similar lesions in children with suspected COVID-19 in Italy. In the series by Galván et al.,11 the pattern ofpseudochilblain lesions was the second most common skinmanifestation (19%). They developed in young patients, gen-erally late on in the course of the disease, and were presentfor a period of 12.7 days, in general, in patients with milddisease or asymptomatic individuals. These lesions weredescribed as painful (32%) or itchy (30%).

From the clinical point of view, the pseudochilblain pat-tern of lesions consists of macules, papules, or plaques,often about a millimeter in size, and usually with a clearlydefined border in the metatarsophalangeal area, althoughthe whole of the finger or toe can be involved (Fig. 1). Often,only some fingers or toes are affected while others com-pletely lack any involvement, and at times, these lesionsmay be accompanied by lesions in the palmar and plantarregion. They usually affect the feet and, to a lesser degree,the hands. Initially purpuric or bluish, they can form blistersor scabs during the course of the disease; at times, they mayresemble multiform erythema13 or vasculitis; in fact, someauthors recognize a multiform erythema type subgroup,13---15

with targetoid or atypical target lesions, which can be asso-ciated with lesions in extensor areas, such as the elbows.In cases with histological study, a lymphocytic infiltrate isreported in the superficial and deep dermis, of perivascu-lar predominance, occasionally associated with edema andsigns of endothelial activation.14 Keratinocyte necrosis andperieccrine reinforcement may be present.15

Alramthan and Aldaraji,16 reporting 2 clinical casesin young adults, proposed the hypothesis, not con-

Cutaneous Manifestations in the Context of SARS-CoV-2 Infection (COVID-19) 737

Table 1 Characteristics of the Skin Manifestations Described in Association With SARS-Cov-2 Infection.

Acral or

Acroischemic

Lesions

Vesicular and

Chickenpox-Like

Lesions

Urticarial Rash Maculopapular

Rash

Livedoid or

Necrotic Lesions

Frequency 19% 9% 19% 47% 6%

Site Acral. Asymmetric

Feet >hands

5% other sites

Trunk (∼100%)

±limbs (∼20%)

No facial or

mucosal

involvement

Predominance on

the trunk,

proximal to the

limbs.

Symmetric

Trunk

Region proximal to

the limbs

No mucosal

involvement

Predominance of

acral region and

region distal to

the legs

Regions with

greater

hydrostatic

pressure or lower

regions

Symptoms Asymptomatic

(∼1/3), painful

(∼1/3), or itchy

(∼1/3)

Mild or

asymptomatic

pruritus (∼2/3),

pain or burning

sensation

Almost constant

pruritus, of

variable intensity

Pruritus (>2/3),

mild to moderate

Pain, burning

Characteristics Macules, papules,

plaques, or

nodules

Erythematous to

purpuric

Small-sized

vesicles. Disperse

Monomorphic

Erythematous and

edematous

papules and

plaques

Erythematous

macules and

papules, often

confluent

Ischemic or

necrotic lesions,

often diffuse

Possible subtypes

and variants

2 possible

patterns:

• Pseudochilblain

lesions (>70%) in

the digital region.

Region distal from

the fingers or

toes. Edematous.

Possible formation

of vesicles,

pustules, and

scabs

• Multiform

erythema-like

pattern (approx.

30%). Plaques

(heels) and palms.

Erythematous,

confluent macules

or papules, with

possible blistering.

No formation of

typical targetoid

lesions and less

extensive than

multiform

erythema

• Generally,

disperse lesions.

Resemble other

viral rashes

• They may have

hemorrhagic

content, be of

larger size, or

show diffuse

coverage of

extensive areas

• Less often,

predominantly

acral vesicles or

pustules

Cases have been

reported of acral

and facial

involvement

Forms have been

described with

perifollicular

predominance, of

the pityriasis

rosea and flexural

type that

resemble SDRIFE

In some cases,

craniocaudal

progression has

been reported

From forms that

resemble livedo

reticularis or

racemosa to areas

of retiform

purpura,

hemorrhagic

blisters, diffuse

ischemia, or

gangrene involving

the distal regions

Demographic

profile

Adolescents or

young adults

No significant

differences

between sexes

Adults, middle age

(30---40 years)

No significant

differences

between sexes

Adults, middle age

(40---50 years)

No significant

differences

between sexes

Adults, middle age

(30---50 years)

No significant

differences

between sexes

Middle aged and

elderly adults

No significant

differences

between sexes

738 J.M. Carrascosa et al.

Table 1 (Continued)

Acral or

Acroischemic

Lesions

Vesicular and

Chickenpox-Like

Lesions

Urticarial Rash Maculopapular

Rash

Livedoid or

Necrotic Lesions

Lag with respect

to respiratory or

systemic

manifestations

Late onset Early onset. After

a few days of

respiratory and

systemic

manifestations

(15% before other

symptoms)

Early onset.

Accompanies

respiratory or

systemic

manifestations, or

precedes them

Accompanies

respiratory or

systemic

manifestations, or

appears a few

days later

Accompanies

respiratory or

systemic

manifestations, or

sometimes with

late onset

Positive for

PCR/serology

<50% (possibly

associated with

late onset)

In favor: clinical

and

epidemiological

evidence, positive

contacts

Frequent,

probably >50%

Frequent,

probably >50%

Frequent,

probably >50%

Very frequent,

probably >75%

Mean duration

(days) of the rash

12.7 (±8) 10.4 (±9.3) 6.8 (±7.8) 8.6 (±6.8) 9.4 (±5.4)

Prognosis It appears to be

associated with

milder disease

(acral ischemic

lesions in patients

with DIC are

excluded from

these cases)

Moderate severity

Recovery without

any scarring

Variable

Cases ranging from

mild-moderate

severity to death

as the outcome

(2% mortality)

Severe cases,

some with death

as the outcome

(10% mortality)

Proposed

treatments

Topical

corticosteroids,

alone or in

combination with

topical antibiotics

Watch-and-wait Oral

antihistamines

Topical

corticosteroids,

oral

antihistamines,

oral

corticosteroids

Support measures

Anticoagulation

measures

Main references 11,13---18 11,19 11,21---23 11,25,30,31 6,34,35

firmed with histology in their own cases, that for-mation of hyaline thrombi in small caliber vesselsof different organs observed in autopsies of patientscould explain the pseudochilblain characteristics of thelesions.

Fewer than half the cases had microbiological or sero-logical test results available (specific PCR or rapid antibodytest for IgM/IgG). In general, when assessed, laboratoryabnormalities or elevations have generally been lacking inmeasures of inflammation such as D-dimer, C reactive pro-tein (CRP), or lactate dehydrogenase (LDH), indicative ofpoor prognosis for this disease. The strongest evidence ofassociation with viral infection was therefore that presen-tation occurred during the pandemic (and in a differentcontext to that of chilblains, in the warmer months thanwhen they usually appear) and a history in the family envi-ronment or personal situation consistent with infection. Theauthors suggested these negative results were due to thelate development of these lesions in the course of the dis-ease; the low sensitivity of the tests used, which has led to

mass recall of some batches; and the rapid disappearanceof antibodies.11,15

Docampo-Simón et al.,17 in the first prospective studyof skin manifestations, found a positive PCR result in only1 of the 38 samples tested. In addition, due to the afore-mentioned technical reasons (time since infection, falsenegatives), the authors considered the possibility that thismanifestation simply has nothing to do with COVID-19. Otherpossible explanations could be a traumatic origin duringlock-down or even the concurrent expansion of anothervirus, such as parvovirus B19. This possible relation with thelock-down period, and not necessarily with COVID-19, hasalso been suggested in a recent series with similar results.18

During the worst weeks of the pandemic, we saw patientswith these characteristics almost on a daily basis in ourclinics. From both the clinical and epidemiological point ofview, the characteristics are consistent with those describedabove. Most of our patients were young, asymptomatic orwith mild symptoms, and not one of them had a seriouscomplication associated with COVID-19.

Cutaneous Manifestations in the Context of SARS-CoV-2 Infection (COVID-19) 739

Figure 2 Disperse monomorphic papulovesicles on the trunk.

Vesicular and Chickenpox-Like Lesions

In 8 Italian centers, clinical data were collected frompatients with COVID-19, with microbiological confirmationby RT-PCR from a nasopharyngeal swab and with no historyof medications that could have triggered chickenpox-likelesions. In total, the study included 22 patients, mainlymales, with a mean age of 60 years. The lag from the onsetof symptoms of COVID-19 to development of skin manifesta-tions was relatively short, 3 days (range, 2 to 12 days). Mostpatients presented with the full clinical manifestations ofthe disease, with general and respiratory manifestations.19

Vesicular lesions, usually monomorphic, appear earlyon and may at times precede other symptoms (in 15% ofpatients),11 although in most cases, up to 79.2% in a seriesof 24 patents reported by Fernandez-Nieto et al.,20 theyoccur at the onset of other symptoms. There is involve-ment of the trunk in almost all cases and in 20% the limbsare also affected (Fig. 2). Exceptionally, facial and mucosalinvolvement have been reported. The skin lesions are barelysymptomatic, but when they do cause symptoms, these areusually mild itching and, to a lesser extent pain or burn-ing sensation.11,19 Although the lesions may be disperse,an extensive disseminated pattern is more frequent, 75%according to Fernandez-Nieto et al. In some patients, thelegs may be affected, or the lesions may present withhemorrhagic content or be large, with a diffuse distribu-tion. The mean duration of skin symptoms is 10.4 days(±9.3).11 In cases in which a biopsy was obtained, thefindings were described as consistent with viral infection,showing vacuolar abnormalities and abnormal maturationof keratinocytes, as well as larger, multinucleated ker-atinocytes, and dyskeratosis.19 There have been no reportsof presence of SARS-Cov-2 confirmed with positive PCR inbiopsies of skin lesions.

Urticarial Rash

Henry et al.21 reported the case of a female patient whodeveloped an urticarial rash, accompanied by odynophagiaand arthralgia, before developing the full clinical manifes-tations of COVID-19. Van Damme et al.22 reported a further2 cases of urticarial rash as the first clinical manifestationof COVID-19, although microbiological confirmation of infec-tion was only obtained in 1 of those, and in both cases the

Figure 3 Maculopapular rash in a patient with COVID-19 asso-

ciated with bilateral pneumonia, who received different drugs.

Differential diagnosis with respect to toxicoderma is difficult.

skin manifestations preceded pyrexia. One of the patientsdeveloped severe respiratory failure, leading to death.

Urticarial rash accounts for 19% of skin manifestationsin COVID-19. In general, these skin manifestations becomeevident more or less at the same time as other generaland respiratory symptoms. Lesions occur predominantly onthe trunk, and involvement of the face and hands is fre-quent, with resolution in approximately 7 days.11 In oneof the cases reported, histological study showed edema ofthe upper dermis and perivascular lymphocytic infiltration,with some eosinophils present.10 Although such lesions maybe associated with worse prognosis in some patients,11 thisis a nonspecific rash, and it has been reported in patientswith a favorable clinical outcome and those with limitedsymptoms.23

There is probably a certain degree of variability in theway in which rashes are reported as urticarial maculopapu-lar because, in the cases described, it is not specifiedwhether the lesions follow a transient course or not. Theseare nonspecific rashes in which it is difficult to establisha solid relationship with viral infection, bearing in mindthat the patients who present with these lesions have oftenreceived a range of treatments such as antiviral agents,antibiotics, hydroxychloroquine, anticoagulants, and sup-port treatments, and these could also trigger skin reactions(Fig. 3). In fact, in a histological study, some cases of vac-uolar interface dermatitis were observed with occasionalnecrotic keratinocytes, findings more reminiscent of a mul-tiform erythematous pattern.24

Maculopapular Rash

This group of lesions includes a heterogeneous group ofrashes that, considered together, and given the difficultyof further subclassification, account for 47% of the skinmanifestations in patients with COVID-19.11 At times, theserashes may be accompanied by a petechial component

740 J.M. Carrascosa et al.

Figure 4 Nonspecific rash, with perifollicular distribution in

a patient with COVID-19.

Figure 5 Multiform erythema-like eruption in a patient with

SARS-CoV-2 infection.

or with macules or more extensive areas with a purpuricappearance. In other cases, the lesions have a markedlyperifollicular distribution (Fig. 4) with variable degreesof scaling, some of which have been reported as simi-lar to pityriasis rosea.25 Infiltrated papules have also beenobserved; these are pseudovesicular lesions or similar toerythema elevatum diutinum or multiform erythema, andthey may occasionally be pruritic (Fig. 5).26 A markedlycraniocaudal development has also been reported, withinvolvement of the folds but without the palmoplantarregion or the mucosa being affected.27,28

Jimenez-Cauhe et al.29 reported the case of a femalepatient who developed a coalescent erythematous-purpuricrash about a millimeter in size, with a flexural distributionpredominantly in the periaxillary region. The authors con-sidered the difficulty of associating the skin manifestationswith viral infection in view of its nonspecific appearance andconcomitant medication use. Other authors have reportedthe appearance of rash that resembles the typical skininvolvement of symmetrical drug-related intertriginous and

Figure 6 Periaxillary exanthematous eruption similar to

SDRIFE.

Figure 7 Livedoid rash with a transient course on the trunk

of a patient with severe COVID-19.

flexural exanthema (SDRIFE), possibly associated with viralinfection, given that the rash resolved despite continued useof the drug.30 We have also observed a similar distribution inour own patients (Fig. 6). From the histological point of view,a range of features have been reported within the group ofmaculopapular rashes, such as a perivascular inflammatoryinfiltrate with discrete lymphocytic exocytosis, marked ves-sel dilatation in the superficial and medial dermis, as wellas lymphocytic vasculitis.31,32

There is limited additional information in these patientsregarding the timing with respect to other clinical man-ifestations or its prognostic or diagnostic value. In mostcases, maculopapular rashes appear either at the same timeas the characteristic respiratory symptoms or a few dayslater.11,28,32,33 However, in our hospital, we have detectedmore or less generalized maculopapular rashes, in somecases similar to multiform erythema, in young patients witha history of mild or even no symptoms, although with epi-demiological evidence of infection with SARS-CoV-2 andthese resemble those that can be seen in other viral infec-tions.

Livedoid or Necrotic Lesions

Livedoid or necrotic lesions are relatively uncommon,accounting for 6% of skin lesions in the series reported

Cutaneous Manifestations in the Context of SARS-CoV-2 Infection (COVID-19) 741

by Galván et al.11 These are lesions usually reported inelderly patients with prior comorbidities and with severeforms of COVID-19 infection. They are considered sec-ondary to vascular micro-occlusion and acral ischemia dueto general deterioration in the patient’s state and/or thecoagulation disorders attributed to COVID-192,5 (Fig. 7).8

However, in some patients, episodes have been reportedof patchy livedo reticularis that presented over the courseof minutes or hours, of an uncertain nature and a benigncourse.35

In the histological study of cutaneous purpuric lesions,a pauci-inflammatory thrombogenic vasculopathy has beenfound, with C5b-9 and C4d deposits, and localization ofviral particles, leading to suspicion of the presence of acatastrophic microvascular lesion caused by complementactivation.6

Conclusions

The SARS-CoV-2 pandemic has had a major impact fromthe healthcare, economic, and societal point of view, andwill probably lead to lasting changes in our generation.Considered initially as of little relevance, the dermatolog-ical manifestations have proved to be varied and complex.Recent efforts to characterize cutaneous involvement inpatients with COVID-19, implemented in a study conductedquickly and rigorously in a full health emergency, has iden-tified 5 main groups of lesion (acral, vesicular, urticarial,maculopapular and livedoid/necrotic lesions).11 Althoughthese manifestations are considered a reflection of differ-ent pathogenic pathways, with a variable implication of theviral infection, inflammatory processes, and vascular andsystemic complications of the disease, there is a substantialknowledge gap in many aspects. Thus, it cannot be ruled outthat acral lesions, reported as characteristic given the epi-demiological evidence rather than microbiological tests inmost cases, may not be directly related to COVID-19. Exten-sive urticarial or maculopapular rashes, often described insymptomatic or even hospitalized patients, may be linkedin many cases to drugs able to trigger them, such ashydroxychloroquine or antibiotics, administered during theCOVID-19 pandemic despite limited evidence of their effec-tiveness. Finally, the heterogeneous set of maculopapularrashes consistent with viral infection, multiform erythema,or SDRIFE, may be associated with other etiologic agentsneglected during the pandemic, as in many cases, microbi-ological or serologic confirmation of SARS-CoV-2 infection islacking. Thus, in the panorama of lesions associated withCOVID-19, for the most part, priority in the internationalliterature during the peak of the pandemic was given torapid publication, even though the description, support, ormethodological rigor were not ideal. Familiarity with theskin manifestations may allow not only greater investiga-tion into aspects still little known in COVID-19, but also mayhelp a more rapid diagnosis and even serve as a prognosticmarker.

Conflicts of Interest

The authors declare that they have no conflicts of interest.

Acknowledgments

We would like to thank Doctors Aram Boada, Isabel Bielsa,María Blanco, Ferran Ballescà, Juli Bassas, Elena del Alcázar,Gonzalo Castillo, Carlos Ferrándiz, María José Fuente, AdriàPlana, Nina Richarz, Verónica Mora, Arantxa Arrieta, andAne Jaka, with whom the authors have worked and sharedknowledge during the peak of the COVID-19 pandemic.

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